13-ethyl-6-oxygenated steroids



United States Patent US. Cl. 260-3974 7 Claims ABSTRACT OF THE DISCLOSURE 135-polycarbonalkyl-17B-hydroxy-17a-alkylor alkynyl- 3,6-dioxygenated gonane derivatives are prepared having hormonal activity.

is R2 wherein the 4,5-position is saturated or double bonded; R is an alpha-hydroxy substituent only when ring A is saturated and provided R is beta-hydroxy or beta-lower alkoxy; R stands for hydrogen, ethynyl or an alkyl of less than six carbon atoms; R is hydrogen; R is selected from the group consisting of hydroxy, lower alkoxy and acyloxy, or together R and R are oxo (=0); R is an alkyl group of 2 to 4 carbon atoms; R is hydrogen; R is selected from the group consisting of hydroxy, lower alkoxy, and acyloxy, or together R and R are OXO (=0); with the wavy bond at R representing alpha or beta configuration; with the proviso that R is beta only when R is a substituent.

Among the suitable alkoxy radicals may be mentioned methoxy, ethoxy, propoxy, butoxy, and the like. Among the suitable acyloxy substituents may be mentioned the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric, hexanoic and enanthic acid), the lower alkenoic acids (e.g., acrylic acid), the cycloalkane carboxylic acids (e.g., cyclobutane carboxylic acid), the cycloalkane carboxylic acids, the monocyclic aromatic carboxylic acids (e.g., benzoic acid), and the monocyclic aryl (lower alkanoic) acids (e.g., phenacetic and fi-phenylpropionic acid).

3,499,015 Patented Mar. 3, 1970 The compounds of this invention can be prepared by employing the novel processes of this invention beginning with compounds of the formula:

wherein R and R are as hereinbefore defined, as starting material.

The compounds of this invention may be prepared according to the process of this invention which may be represented by the following reaction sequence wherein R and R are as hereinbefore defined:

OH R4 I on on n 5 III on on ch 65* IV v In the first step of this invention, 13-lower alkyl-17a-lower alkyl-l7-hydroxygon-4-en-3-one (Compound I) is treated with an alkoxide of an alkali metal (e.g., potassium t-butoxide) in an inert solvent and then acidified to yield the 13-lower alky1-l7a-lower alkyl-17-hydroxygon-5-en- 3-one (Compound II).

Compound II is then interacted with an organic peracid (e.g., perbenzoic acid, haloperbenzoic acid, perphthalic acid and per (lower alkanoic) acids), in an inert medium to yield inter alia, the 5,6-epoxide compound (Compound III).

These epoxide compounds are then opened by a method such as heating under reflux conditions in an inert organic solvent for a period of about 15 to 25 hours or by heating under reflux conditions in the presence of an acid such as m-chlorobenzoic acid to yield the 6u-hydroxy steroid (Compound IV) of this invention. The fiu-hydroxy 3 steroid may be treated with an oxidizing agent such as chromic acid to yield the 6-oxo steroid (Compound V), which is also a final product of this invention.

The 6a-hydroxy compounds (IV) of this invention may be acylated to the corresponding 6-ester steroids as shown in the following reaction step:

OH OH l--- 1 ()H (5 acyl IV VI Thus, to prepare the 6-acyloxy derivatives (VI) wherein the acyl radical corresponds to the acyl radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms, either the acyl halide or acid anhydride of a lower alkanoic acid, lower alkenoic acid, monocyclic aryl carboxylic acid, monocyclic aryl lower alkenoic acid, cycloalkane carboxylic acid or cycloalkene carboxylic acid is employed as a reactant.

In order to prepare 3-hydroxy-6-oxygenated derivatives, for example, Compound VII shown below, the corresponding 3-keto steroid may be reduced with a reducing agent such as a metal hydride (e.g., lithium aluminum hydride) or an alkali metal borohydride (e.g., sodium borohydride). Such a reaction step may be illustrated as follows:

OH OH IV VII It is also possible to prepare fifi-oxygenated compounds.

These compounds may be prepared according to the following reaction sequence from Compound HI:

III

Compound VIII is reacted with dilute hydrochloric acid in ethanol, the 6fi-alkoxy-gon-4-ene is formed (Compound IX), Y having the same meaning as before.

Additionally, the 5,6-epoxide steroid (III) may be treated with oxalic acid in an aqueous medium to produce a 5a,6j8,l75-trihydroxy gonane (X) which is useful as an intermediate for preparing a 3-keto-6u-hydroxy-gon- 4-ene according to the following reaction sequence:

Thus, the trihydroxy Compound X, prepared as indicated above, may be reacted with dilute hydrochloric acid in ethanol, producing the Compound XI which is the 3- keto6a-hydroxy-gon-4-ene mentioned above.

The following examples illustrate the invention (all temperatures being in centigrade).

EXAMPLE 1 13,l7a-diethyl-l7-hydroxygon-5-en-3-one To 1.0 gm. of 13,l7a-diethyl-17-hydroxygon-4-en-3-one dissolved in 20 ml. of dry diglyme is added 3.75 gm. of potassium t-butoxide. The mixture is stirred under nitrogen at room temperature for a period of about minutes.

ml. of ice cold 10% aqueous acetic acid is added rapidly to the mixture and then the mixture is poured into a saturated sodium bicarbonate solution and extracted with ether. The ether extract is washed with brine, dried with sodium sulfate and evaporated to dryness under vacuum. The residue is crystallized from acetonitrile to yield 0.595 gm. of l3,17a-diethyl-171hydroxygon-5-en-3-one having a melting point about -173".

REE}? 2.40 In (e=l,265) due to 7.6% of starting material.

REE; 2.90

5.87, 8.46, and 10.23

EXAMPLE 2 13-ethyl-17ot-butyl-l7-hydroxygon-5-en-3-one Following the procedure of Example 1 but substituting 13-ethyl-17u-butyl-l7-hydroxygon-4-en-3-one for 13,170;- diethyl-l7-hydroxygon-4-en-3-one there is obtained 13- ethyl-17u-butyh17-hydroxygon-5-en-3-one.

EXAMPLE 3 13,17a-dipropyl-17-hydroxygon-5-en-3-one Following the procedure of Example 1 but substituting 13-propyl-l7u-propyl-17-hydroxygon-4-en-3-one for 13, 17a-diethyl-17-hydroxygon-4-en-3-one there is obtained 13,17a-dipropyl-17-hydroxygon-5-en-3-one.

EXAMPLE 4 13-ethyl-17-hydroxygon-5-en-3-one Following the procedure of Example 1 but substituting 13-ethyl-17-hydroxygon-4-en-3-one for 13,17a-diethyl-17- hydroxygon-4-en-3-one there is obtained l3-ethyl-l7-hydroxygon5-en-3-one.

EXAMPLE 5 5a,6oz-epoxy-l3, l7u-diethyl-17-hydr0xygonan-3-one Analysis.Calcd. for C H O (percent): C, 75.86; H, 9.70. Found (percent): C, 75.71; H, 9.98.

EXAMPLE 6 5a,6a-epoxy-13-ethyl-17a-butyl-17-hydroxygonan-3-one Following the procedure of Example 5 but substituting 13-ethyl-17a-butyl-17-hydroxygon-5-en-3-one for 13,17zxdiethyl-17-hydroxygon-5-en-3-one there is obtained 5 a,6uepoxy-13-ethyl-17a-butyl-l7-hydroxygonan-3-one.

EXAMPLE 7 5 a,6a-epoxy-l3,17a-diprpyl-l7-hydroxygonan-3-one Following the procedure of Example but substituting 13,l7a-dipropyl-l7-hydroxygon-5-en-3-one for 13,17u-diethyl17-hydroxygon-5-en3-one there is obtained 5a,6aepoxy-13,17a-dipropyl-17-hydroxygonan-3-one.

EXAMPLE 8 Se m-epoxy-13-ethyl-l7-hydroxygonan-3-one Following the procedure of Example 5 but substituting 13-ethyl-l7-hydroxygon-5-en-3-one for l3,l7a-diethyl-l7- hydroxygon-5-en-3-one there is obtained 5a,6 x-epoxy-l3- ethyl-l7-hydroxygonan-3-one.

EXAMPLE 9 13,17a-diethyl-6a, l7-dihydroxygon-4-en-3-one To 7.0 gm. of 13,17a-diethyl-17-hydroxygon-5-en-3-one dissolved in 250 ml. of benzene is added 4.25 gm. of m-chloroperbenzoic acid in 100 ml. of benzene. The mixture is stirred at room temperature for 20 minutes to form the 50:,60L-6POXld6 and then refluxed for 20 hours. The mixture is then cooled and poured into an aqueous bicarbonate solution. The organic layer is separated, washed with water, dried and the solvent removed under vacuum. The solid residue is recrystallized from methanol-ethyl acetate to yield 4.44 gm. of l3,17a-diethyl-6a,17- dihydroxygon-4-en-3-one having a melting point of about 22823l.

REE; 3.05 6.04, and 6.l9,u.

A3222? 44 u (e=l4,900). 77.92 (m.,

Analysis.-Calcd. for C H O C, 75.86%; H, 9.70%. Found: C, 75.86%; H, 9.65%.

EXAMPLE 10 13-ethyl-17a-butyl6a,17-dihydroxygon-4-en-3-one To 7.0 gm. of 5a,6u-epoxy-13-ethy1-17u-butyl-17-hydroxygonan-3-one dissolved in 25 0 ml. of benzene is added 4.3 gm. of m-chlorobenzoic acid in ml. of benzene. The mixture is stirred at room temperature for 20 minutes and then refluxed for 20 hours. The'mixture is cooled and then poured into an aqueous sodium bicarbonate solution. The organic phase is separated and the solvent is removed under vacuum to yield l3-ethyl-17a-'butyl-6a,17- dihydroxygon-4-en-3-one.

EXAMPLE 1 l 13, l7a-dipropyl-6a,17-dihydroxygon-4-en-3-one Following the procedure of Example 9 but substituting 13,l7ot-dipropyl-17-hydroxygon-5-en-3-one for 13,17oc-dlethyl-17-hydroxygon-5-en-3-one there is obtained 13.17adipropyl-6ot, 17 -dihydroxygon-4-en-3-one.

EXAMPLE 12 13-6thyl-60t, 17-dihydroxygon-4-en-3-one Following the procedure of Example 9 but substituting 13-ethyl-l7-hydroxygon-5-en-3-one for 13,17oc-di6thYl-l7- hydroxygon-5-en-3-one there is obtained l3-ethyl-6a,17- dihydroxygon-4-en-3-one.

EXAMPLE 13 13,17a-diethy1-6u,17-dihydroxygon-4-en-3-one,6-acetate To mg. of l3,17a-diethyl-6a,17-dihydroxygon-4-en- 3-one in 5 ml. of pyridine is added 1 ml. of acetic anhydride. The mixture is stirred at room temperature for 24 hours.

Methanol is added to the mixture which is then added to water and extracted with ether. The organic layer is washed with Water, 2% sulfuric acid solution, dried and then the solvent is removed under vacuum to yield 90 mg. of l3,l7a-diethyl-6ot,17-dihydroxygon-4-en-3-one,6- acetate having a melting point of about 136-138;

Afif; 2.95

5.74, 6.03, 6.16 and 8.l0,u.;

kEtOH max.

(6: 14,220); 1- CDCI 4.06 (m., 4-H).

In similar manner by substituting any other acid anhydride or acyl chloride for the acetic anhydride in the procedure of Example 13, the corresponding ester is formed.

Similarly the compounds of Examples 10 through 12 may be converted to their acetate derivatives.

EXAMPLE 14 13, l7rx-diethyl-17-hydroxygon-4-en-3,6-dione To 2.5 gm. of 13,17a-diethy1-6a,17-dihydroxygon-4-en- 3-one dissolved in 500 ml. of acetone and cooled at 0 C., is added 2.5 ml. of 8 N chromic acid. The reaction mixture is stirred for 10 minutes, 12.5 ml. of isopropanol is added and the mixture is poured into water. The organic layer is dried and then washed through a column of neutral alumina with ether. The solvent is evaporated under vacuum and the solid residue is triturated with ether to yield 1.85 gm. of 13,l7ot-diethyl-l7-hydroxygon-4-en-3,6- dione having a melting point of about 168-171";

kffif; 2.85 5.96, and 625p.

AELOH max.

(e=10,320); CDCl 3.54 (d., 4-H) (1:2 cps.).

Analysis.Calcd. for C H O C, 76.32%; H, 9.15%. Found: C, 76.19%; H, 9.08%.

Oxidation of the products of Examples 10 and 11 with chromic acid according to the procedure of Example 14 gives, respectively, the products of the following Examples l and 16.

Starting material is Example the product of No. Example No. Product 15 10 13Ethyl-17a-hutyl-17-hydroxygon-4.-en-3,6- tone. 16 11 13,lf7a-dipropyl-lF-hydrowgon--eu-iifidrone.

EXAMPLE 17 13,17 a-diethyl-3,6a,17fl-trihydroxygon-4-ene Similarly the products of Examples 10 through 12 may be reduced with sodium borohydride to yield the respective 3,6,17-trihydroxylated compound.

EXAMPLE l8 13,17a-diethyl-5a,6,17{3-trihydroxygonan-3-one To a solution of 0.150 gm. of 13,17u-diethyl-5a,6aepoxy-17-hydroxygonan-3-one in 25 ml. of tetrahydrofuran is added 0.10 gm. of oxalic acid in 25 ml. of water. The mixture is stirred 2 hours poured into water and extracted with ether.

The ether extract is washed with water, dried, and the solvent is evaporated in vacuo. The residue is crystallized from acetone to yield 0.06 gm. of 13,17a-diethyl-5u,6/3, 17fi-trihydroxy-gonan-3-one having a melting point of about 266-268";

and 5.85

Analysis.Calcd. for C H O C, 71.90%; H, 9.78%. Found: C, 71.77%; H, 9.43%.

EXAMPLE 19 l3,l7u-diethyl-17-hydroxy-6,6-methoxygon-4-en-3-one (a) Preparation of 13,17a-diethyl-5a-17-dihydroxy-6B- methoxygonan-3-one.To 0.5 gm. of 13,17oz-dl3thYl-5tx- 6ot-epoxy-l7-hydroxygonan-3-one in 50 ml. of methanol is added 0.5 gm. of oxalic acid dihydrate in 50 ml. of methanol. The mixture is stirred for 30 minutes poured into aqueous sodium bicarbonate and then extracted with ether. The organic layer is washed with water, dried and the solvent is evaporated in vacuo. The residue is crystallized from ether to yield 0.14 gm. of 13,17oz-dl6lhYl-5u-17-dihydroxy-6fi-methoxygonan-3-one having a melting point of about 182185;

KB: AHID-X.

3.02 and 586,1.

Analysis.--Calcd. for C H O C, 72.49%; H, 9.96%. Found: C, 72.49%; H, 9.88%.

(b) Preparation of 13,17 ot-diethyl-17hydroxy-6fl-methoxygon-4-en-3-one.To 1.07 mg. of 13,1706-dl6thYl-50L- 17-dihydroxy-6,8-rnethoxy-gonan-3-one dissolved in 100 ml. of 95% ethanol is added 1 ml. of concentrated hydrochloric acid. The mixture is allowed to stand at room temperature for hours and then extracted with ether. The

ether extract is evaporated in vacuo to yield 13,170C-dlethyl-l7-hydroxy-6B-methoxygon-4-en-3-one;

AEZF+HG1 242 318, and 366 (e=11,570, 1,365, and 1,700).

Similarly the 50,6ot-6POXY compounds of Examples 6 through 9 may be converted to their corresponding Swhydroxy and 65-methoxy derivatives.

Similarly by following the procedure of Example 19, but substituting ethanol, propanol, butanol, and the like, for methanol, the corresponding fi-ethoxy, 6,8-propoxy, and 65-butoxy derivatives may be prepared.

The 6-keto and the 6a-oxygenated gon-4-enes of the invention are physiologically active substances found to possess significant progestational activitiy and therefore useful experimentally in warm-blooded animals, for example, female rabbits, and may also be used in comparing such actions with other or known steroidal compounds having generally similar or possibly equivalent chemical structure. The standard Clauberg test procedure may be followed in determining progestational activity.

The saturated gonanes are useful as intermediates from which 6u-oxygenated-gon-4-enes may be prepared as already described and having the utility indicated above.

In using the active compounds of the invention, they may be formulated in essentially the same manner as the known progestational agents, as for example, progesterone, the concentration and/or dosage being based on the activity of the compound selected.

The invention may be variously otherwise embodied within the scope of the appended claims.

The invention that is claimed is:

1. A compound having the formula:

in which R is hydroxy when the A ring is saturated and R is beta-hydroxy; R is hydrogen; R is hydroxy, acetoxy, or R and R together are oxo; R is ethyl; R is hydrogen; R is hydroxy, or R and R together are oxo; the dotted line indicating that the 4,5-position may be single or double bonded, and the wavy line indicating an alpha or beta configuration; with the proviso that said wavy line is alpha when the A-ring is unsaturated and it is beta only when the A-ring is saturated and R is alpha-hydroxy.

2. A compound of claim 1; having the formula:

in which R is hydrogen; R is hydroxy or acetoxy or R and R together are oxo; R is ethyl; R is hydrogen; R is hydroxy or R and R together are 0x0.

3. As a compound of claim 1; 13,17ot-diethyl-6u,l7-di hydroxygon-4-en-3-one.

4. As a compound of claim 1; l3,17a-diethyl-6a,17-dihydroxygon4-en-3-one,6-acetate.

5. As a compound of claim 1; 13,17nt-dicthyl-17-hydroxygon-4-en-3,6-dione.

6. As a compound of claim 1; 13,l7a-diethyl-3,6a,17- trihydroxygon-4-ene.

9 10 7. As a compound of claim 1; 13,17a-diethy1-5a,6fi, 3,032,565 5/1962 Dodson et a1 260--397.4 17,8-trihydroxygonan-3-one. 3,231,589 1/1966 Greenspan 260397.4

References Cited LEWIS GOTTS, Primary Examiner ST P 5 Assistant Examiner 2,312,344 3/1943 Logemann 260239.55

3,004,045 10/1961 Zeelen 260-3974 260-239.55, 397.5, 999

g;;g-; UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,499,015 Dated ILagCh .5. i970 )George H. Douglas, Uharles R. walk, Herchel smith It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

claim 1 should read:

A compound having the formula:

in which R is hydroxy when the A ring is saturated and R is beta-hydroxy; K is hydrogen; R is hydrox acetoxy,

or R and K together are oxo; R is ethyl; R is hydrogen; R is hydroxy, or R and K together are oxo; the dotted line indicating that the 4,5-position may be single or double bonded, and the wavy line indicating an alpha or beta configuration; with the proviso that said wavy line is alpha when the A-ring is unsaturated and it is beta only when the A-ring is saturated and ii is alpha-hydroxy.

SIGNED AND I. SEALED fidwdumkmulls. mma. mm 1120mm. a 

